Clostridium difficile (C. difficile or C. diff) is a Gram-positive, spore-forming bacterium that causes hospital-acquired as well as community-acquired enteric infections. Infections can be asymptomatic but generally lead to C. diff-associated diarrhea, pseudomembranous colitis, colitis and death (Halsey, J. 2008, Am J Health Syst Pharm 65(8):705-15; Lessa, F. C. et al. 2012, Clin Infect Dis. 55(Suppl 2): S65S70).
C. difficile infection is often but not always induced by antibiotic disruption of the colonic flora through the use of antibiotics such as clindamycin, cephalosporins, and fluoroquinolones. This perturbation in the colonic microenvironment, along with exposure to C. difficile spores, leads to mucosal C. difficile colonization. This colonization may result from the presence of a pre-existing antibiotic resistant C. difficile or concomitant exposure to C. difficile spores, particularly in hospitals. Approximately one-third of all patients that become colonized develop CDAD, which can result in severe diarrhea, perforation of the colon, colectomy and death. CDAD results from the acquisition and proliferation of C. difficile in the gut, where C. difficile bacteria produce toxin A and toxin B, two important virulence factors of CDAD. Toxins A and B of C. difficile show considerable sequence and structural homology. Both have a C-terminal receptor-binding domain containing multiple repeating sequences, a central hydrophobic domain and an N-terminal glucosyltransferase domain. The receptor-binding domain mediates binding of the toxins to intestinal epithelial cells via host receptors that remain poorly defined in humans. Following internalization via an endosomal pathway, the central hydrophobic domain inserts into the membrane of the endosome. The acidic pH of the endosome triggers pore formation and translocation of the amino-terminal domains of the toxins into the cytosol. Glucosylation of the cytosolic target Rho GTPases leads to disruption of the cytoskeleton and cell death. Toxins A and B demonstrate different pathological profiles and have potential synergy in causing disease.
Current treatment for C. difficile infection (CDI) is the use of certain antibiotics, such as for example but by no means limited to Metronidazole, Vancomycin, and Fidaxomycin, either alone or in combination. However, efficacies of these antibiotics are limited by incomplete response rates with increasing re-infection and recurrence rates. The antibiotic therapy does not provide complete protection to all patients; as a result, 25-40% of patients suffer from C. difficile recurrent infections (Figueroa, I. et al 2012, Clin Infect Dis. 55 Suppl 2:S104-9).
Of great concern, a sharp rise in the rate of C. difficile infection in patients with inflammatory bowel disease (IBD) in recent years. (Rodemann J F et al, 2007; Odes, S L et al. 2011, Hanada et al., 2017). Prior antibiotic use is not detected in 40% of C. difficile outbreaks in IBD patients and many infections are in fact community-acquired as opposed to hospital-acquired C. difficile infections.
Inflammatory Bowel Disease (IBD) is an umbrella term used to describe disorders that involve chronic inflammation of the digestive tract. IBD is generally attributed to an inappropriate immunologic response to otherwise commensal flora in a genetically susceptible host (Hanada et al., 2017). Symptoms of IBD most commonly include fever, vomiting, diarrhea, bloody stool, abdominal pain and weight loss. Types of IBD include ulcerative colitis and Crohn's disease.
Ulcerative colitis causes long-lasting inflammation and sores (ulcers) in the innermost lining of the large intestine (colon) and rectum. UC is usually characterized by inflammation of the colon and the rectum.
Crohn's disease is characterized by inflammation of the lining of the digestive tract, which often spreads deep into affected tissues. CD commonly manifests as inflammation of the small intestine, but can affect other parts of the body as well.
UC and CD are commonly regarded as autoimmune diseases, with evidence suggesting they are the result of misdirected immune response. The etiology of IBD appears to involve complex interactions of genetic predisposition, environmental factors, disruption of the intestinal microbiome and an overly aggressive immune response. In addition, evidence linking the ability of intestinal epithelial cells to modify the mucosal immune response, may suggest an invasive bacterial pathway. Imbalance in intestinal microbiota of gut friendly bacteria destroyed by antibiotics as well as opportunistic pathogens are implicating factors as well (U.S. Pat. No. 9,694,348). Specifically, patients with IBD have been reported to have an abnormal gut microbiota. Whether this altered flora is the cause or the result of chronic inflammation remains unclear.
Patients with IBD have a higher incidence of CDI than persons without IBD. Additionally, IBD patients with CDI have poorer outcomes, including longer length of hospital stay, higher colectomy rates and increased mortality (Hanada et al., 2017).
As such, IDB is assumed to predispose individuals for CDI. Reductions in gut microbial diversity have been identified in IBD patients. Although a causative role for this dysbiosis in the development of IBD has not been well established, it is plausible that dysbiosis may play a role in increasing CDI in IBD patients (D'aoust et al., 2017). The overlap in symptomatology between CDI and IBD flare or relapse complicates the diagnosis of CDI in IBD patients. CDI and acute inflammatory colitis are clinically indistinguishable (D'aoust et al., 2017), both being characterized by diarrhea, abdominal pain, fever and leukocytosis (Nitzan et al., 2013). Despite this, CDI is typically treated with administration of antibiotics and/or fecal microbiota transplantation while IBD is primarily treated with corticosteroids or other immunosuppressive therapies. In fact, one recommended treatment for CDI overlaying IBD is antibiotic therapy followed shortly thereafter with immunosuppressive therapy (D'aoust et al., 2017). Others suggest that immunosuppression be maintained but not escalated in instances where CDI is superimposed over IBD (Nitzan et al., 2013).
In one study, of 124,570 hospital discharges, 2.3% were diagnosed as having both C. difficile and IBD, 36% C. difficile alone and 62% IBD alone. Multivariate analysis of patients in the C. difficile-IBD group had four times greater mortality than patients admitted for IBD alone (OR 4.7) or C. difficile alone (OR 2.2) (Saidel-Odes et al., 2011, Annals of Gastroenterology 24: 263-270).
Despite this, the prior art remains uncertain as to whether C. difficile is a cause of IBD or a consequence of the inflammatory state in the intestinal environment (Nitzan et al., 2013). Specifically, it is hypothesized that the association between IBD and C. difficile may be due to different factors, such as drugs that are used for the treatment of IBD that might alter the intestinal flora or promote colonization, altered immune and nutritional status, frequent hospitalization and even genetic predisposition.
Detection of C. difficile in IBD patients is not easy, as there is no specific dependable clinical picture or stool characteristic. In patients with IBD, the chance of C. difficile infection is greater, although why this occurs is not understood. In one study, qPCR detected C. difficile in 34 of 37 patients with UC who had not been exposed to antibiotics, whereas the toxin test for C. difficile was positive in only 8 of the 37 patients (Saidel-Odes et al., 2011).
Furthermore, there are no studies evaluating treatment of the asymptomatic carriage of C. difficile. The prior art is unclear if treatment of asymptomatic C. difficile carriers would have any impact on IBD disease or the development of symptomatic CDI; however, in the general population, carriage of C. difficile in the absence of symptoms is considered to carry a protective effect against future symptomatic CDI, although this protective effect has not been studied in the IBD population (D'aoust, 2017).
C. difficile infection now poses a serious problem in IBD patients. There is an alarming increase in morbidity, mortality, need for surgery, and health care cost resulting from C. difficile colitis occurring in IBD patients compared with non-infected IBD subjects; therefore, C. difficile now presents an important public health issue for gastroenterologists.
In IBD patients, the early identification and treatment of C. difficile superinfection is clearly important to avoid serious outcomes. Given the changing epidemiology of the C. difficile infection the most important step is to treat C. difficile infection in order to avoid potential complication in IBD patients.